Neurological Manifestations of Human Immunodeficiency Virus Presenter - Dr.Garima Aggarwal Moderator - Dr (Brig) Rajesh Kakkar Dr.Manish Mittal
Oct 19, 2014
Neurological Manifestations of
Human Immunodeficiency Virus
Presenter - Dr.Garima AggarwalModerator - Dr (Brig) Rajesh Kakkar
Dr.Manish Mittal
HIV is the most common viral infection of the nervous system, affecting both the CNS and PNS.
Upto 50% of HIV patients have clinically apparent neurological disease.
Upto 20% of HIV patients present for the first time with neurological manifestations.
Upto 90% of HIV patients have neuropathological changes on autopsy.
India has the second largest burden of HIV related pathology next to sub-Saharan Africa. Neurological complications associated to HIV-1 infections, are very common in our clinical setting.
NEUROPATHOGENESIS
Nervous System effects of HIV infection
DIRECT INDIRECTHIV virus and its products Oppurtunistic infections
HIV associated Neoplasms
Cells affected by HIV - Perivascular Macrophages Monocytes from blood Microglial cells ?Astrocytes
NEUROPATHOGENESIS
CLASSIFICATION OF NEUROLOGICAL MANIFESTATIONS OF HIV
HIV can involve disorders of both the CNS and PNS.
Classification based on the neuroanatomical localization and clinical syndromes associated -
BRAIN Dementia Space occupying lesions Encephalitis Stroke like syndromesMENINGES MeningitisSPINAL CORD Myelopathy RadiculopathyPERIPHERAL NERVES Peripheral Neuropathy Inflammatory Demyelinating Polyneuropathies Toxic NeuropathyMUSCLE Polymyosistis , Pyomyositis HIV associated Wasting Syndrome
Neurological Manifestations of HIV involving the
BRAIN
*AIDS defining illnesses are marked in RED
• HIV Encephalopathy/ ADC• Progressive Multifocal Leuco-
Encephalopathy• Tuberculosis• Neurosyphilis• Lymphoma
DEMENTIA
• Abscesses • Infective Granulomas• Neoplastic• Others
SPACE OCCUPYING
LESIONS
TuberculosisListeriaNocardiaE.Coli
ToxoplasmaAspergillusCandidaCryptococcus
Primary CNS LymphomaSecondary MetastasisMetastatic Kaposi’s SarcomaGlioma
PMLE, Varicella Zoster, CMV
BRAIN
• CMV Encephalitis• PMLE• HSV , VZV• Toxoplasma Encephalitis• Aspergillus encephalitis• Metabolic Encephalitis• IRIS
ENCEPHALITIS
• Granulomatous Angitis – AIDS associated• Infectious Vasculitis – Tb, Neurosyphilis,
Aspergillus, Mucor• Varicella Zoster Virus Vasculitis• Bacterial Endocarditis, non bacterial
thrombotic endocarditis• Venous thrombosis – Hypercoagulable states• HIV asso. Thrombocytopenia• DIC• METASTATIC- Kaposi’s Sarcoma, PCNSL• Coagulopathy
STROKE Like Syndromes
ISCHEMIC
HEMO.
BRAIN
Neurological Manifestations of HIV involving the
MENINGES
• HIV Seroconversion Illness- Aseptic meningitis
• Pneumococcal, Meningococcal• E.Coli• Klebsiella• Listeria
ACUTE
• Mycobacterium tuberculosis• Mycobacterium Avium complex• Cryptococcus• Candida• Syphilis• Nocardia• Metastatic Meningitis - Lymphoma
CHRONIC
MENINGITIS
Neurological Manifestations of HIV involving the
SPINAL CORD
• Vacoular MyelopathyHIV associated
• CMV Myelopathy• Varicella Zoster Virus• Herpes Simplex Virus• HTLV 1 and 2• Neurosyphilis
INFECTIONS
• Lymphoma/metastasis associated Myelopathy
NEOPLASTIC
• Vitamin B 12 DeficiencyMETABOLIC
MYELOPATHY
Neurological Manifestations of HIV involving the
PERIPHERAL NERVES
• AIDP• CIDP• Vasculitic Neuropathy• Cranial Mononeuropathy• Multiple mononeuropathies• Plexopathy – Brachial, Lumbosacral
EARLY STAGES- Immune
Dysregulation
• Distal Sensory Polyneuropathy• Autonomic Neuropathy
MID STAGE – HIV Replication driven
• CMV polyradiculopathy, Mononeuritis Multiplex
• Syphilitic Polyradiculomyelitis• Tuberculous Polyradiculomyelitis• Zoster ganglionitis• Lymphomatous Polyradiculopathy• AIDS Cachexic neuropathy• ALS like motor neuropathy
LATE STAGES – Oppurtunistic
Infections, Neoplasms
• Nucleoside Reverse Transcriptase Inhibitors – Didanosine, Zalcitabine, Stavudine
• Other Concomittantly used drugs – Vincristine, Isoniazid, Ethambutol, Thalidomide
ALL STAGES (TOXIC NEUROPATHY)
NEUROPATHY
Neurological Manifestations of HIV involving the
MUSCLES
• HIV Polymyositis• CMV Polymyositis• Pyomyositis• AIDS cachexia- HIV associated
Wasting Syndrome
INFECTION
• ZIDOVUDINE• Others especially NRTIS
DRUG INDUCED
MYOPATHY
Some commonly encountered Neurological Manifestations
Of HIV
In Clinical Practice
ASEPTIC HIV MENINGITIS 10-15% of patients with Acute HIV Seroconversion illness present
with meningtisPATHPHYSIOLOGY – Immune mediated illnessCLINICAL FEATURES Headache – severe and protracted, isolated persistant headacheSigns of meningeal irritation – nausea, vomiting, photophobiaAcute Seroconversion illness – Flu like febrile illnessPreserved alertness and cognitionMay be associated with features of EncephalitisCranial nerve Involvement may be seen – CN VII, rarely V and/or VIII
It is a diagnosis of exclusion.
ASEPTIC MENINGITIS continued INVESTIGATIONS1. LP – CSF sugar - Normal (40-70mg/dl) protein - Elevated but <100mg/dl (15-50mg/dl) cells - lymphocytic pleocytosis (0-5 Mono/mm3)2. Intrathecal anti HIV IgG 3. Serum P 24 capture assay, HIV RNA level
TREATMENTNo specific therapy is needed.Resolves in 2-4 months without treatment.
HIV ENCEPHALOPATHY/ AIDS DEMENTIA COMPLEX
In the era of HAART, 10-20% of HIV patients are affected by it. It is the first manifestation of AIDS in upto 3 % of HIV patients Associated wth CD4+ T cell count of < 200/mm3 It s considered part of the HIV associated Neurocognitive
Impairment spectrum
PATHOGENESIS – neuropathogenesis as described above.White matter – pallor, multinucleated cell encephaltis, vacoular
changes, focal necrosis and neuronal loss. The cerebral cortex is relatively spared.Areas affected- subcortical structures of brain and spinal cord.
Assymptomatic Minor Cognitive Motor Dysfunction AIDS Dementia Complex
HIV associated NCI, progresses with increased viral load and immunosuppression
HIV ENCEPHALOPATHY continuedCLINICAL FEATURESCognitive impairment – Forgetfulness
Decreased Attention and Concentration Inability to perform complex task Decreased Sexual drive and disrupted Sleep
Mild mania and AgitationMotor Dysfunction- Poor balance
Gait incoordination- slow and rigid gait Slowness of movements
Postural tremors Choreoform movements, myoclonic jerks
Vegetative state- Bowel and Bladder incontinence Unable to Ambulate
lying in bed mute with vacant stare
There are no specific diagnostic criteria for HIV Encephalopathy. Diagnosis of dementia – demonstrating a decline in cognition
CLINICAL STAGING OF HIV ENCEPHALOPATHYSTAGE Mental Function Motor Function
STAGE 0 Normal Normal
STAGE 0.5 Absent, Minimal or Equivocal symtoms
Slowed ocular and extremity movements
STAGE 1 Able to perform all but the demanding aspects.Unequivocal func. and intellectual impairment
Unequivocal motor impairment
Can walk without assistanceSTAGE 2 Performs basic self care
Cannot work or maintain demanding aspects of daily life
AmbulatoryMay require a single prop
STAGE 3 Major Intellectual incapacity Major motor disabilityCannot walk unassisted
STAGE 4 Intellect, social comprehension and output at rudimentray level
Paraparetic or paraplegic with bowel, bladder incontinence
INVESTIGATIONS – testing done only to exclude other diagnosis
1. Neuropsychological testing – MMSEIt is advisabele in all patients with HIV to have a baseline MMSE.2. CT / MRI - Diffuse cerebral atrophy
Patchy or diffusely abnormal signals esp on FLAIR –(Hemispheric white matter +/- basal ganglia and thalamus) Basal Ganglia calcification – in children
3.CSF findings – sugar - normal protein - mildly elevated cells - lymphocytic pleocytosis special tests – HIV IgG synthesis Oligoclonal bands HIV DNA amplification
Quantitative CSF-HIV Burden others MCP1, neopterin, Quin. Acid, Beta2MGThe practical utility of special CSF testing is uncertainNo absolute correlation exists between CSF HIV burden and disease severity
Non specific CSF changes
TREATMENT HAART – HAART improves neuropsychological performance
(Larussa etal 2006) - upto 50% reduction in HIV enceph. since HAART
- simpler regimens with least number of drug side effects - Drugs with high CSF penetration should be used (Zidovudine, Stavudine, Lamivudine, efavirenz, nevirapine) Neuroleptic medication- for patients with psychobehavorial dys.
- they have increased sensitivity to EPS side effects of neurleptic drugs
- TCAs and SSRIs - Clozapine and Haloperidol
Anticonvulsant – Gabapentin and topiramate are preferred Psychological support, assisted living.
CRYPTOCOCCAL MENINGITIS Initial AIDS defining illness in 2% of patients More common with CD4+ T cell count of <100/mic.l CLINICAL FEATURES Subacute onset
Signs of meningeal irritation – fever, stiff neck,vomiting, photophobiaCryptococcomas and Cranial nerve involement rarely
Head to Toe examination for associated infection Skin lesions, like Molluscum contagiosum Palatal and oral ulcers Myocarditis Pulmonary involvement – in 1/3rd of case Gastroenteritis Prostatitis – prostate may serve as reservoir for smoldering infection
INVESTIGATIONS1. CT/MRI – Hydrocephalus
Gelatinous pseudocysts Cryptococcomas
only nonspecific Cerebral Atrophy2. CSF - sugar - decreased
protein - elevated protein cells - monomuclear pleocytosis India ink smear – nonspecific
CSF cryptococcal antigen (CrAg) – sensitivity 95% Fungal CSF culture for Cryptococcus – gold standard
Complications of Cryptoccal meningitis
D/D TbM
D/D Aspergillus, C.immitus, Candida, H.Capsulatum, Naeglaeria
CT brain showing - 1.Gelatinous Pseudocyst( formed by confluence of dilated perivascular spaces).2.Sites: Basal ganglia, cerebral cortex, cerebellum and midbrain. No contrast enhancementMRI: Cyst are of CSF intensity
TREATMENTAmphotericin B +/- Flucytosine
(0.5 to 0.7 mg/kg/day) ( 75 to 150 mg/kg/day)
x 2 to 3 weeks Fluconazole 200mg P/O BD
x upto 3 monthsMaintainence therapy -Fluconazole 200mg P/D OD (1st line)
Amphotericin/Itraconazole weekly (2nd line)
Continue till the CD4+T cell count >200cells/micr.l Increased ICP – Medical- corticosteroids and Acetazolamide Repeated Lumbar punctures, VentriculostomyAcute mortality approaches 30% and is related to inceased ICP
Renal insufficiencyHypokalemiaHypomagnesemia
Hematological Toxicity
TOXOPLASMOSIS of the BRAIN Associaterd with CD4+T cell count < 100cells/micr.l Most commmon cause of focal intracranial masses in patients with
AIDSPATHOGENESISIt almost always occurs as a Recrudescence of previously acquired
infection.It is 10 times times more commmon in patients with Ab to Toxoplas.CLINICAL FEATURES FEVER
HEADACHE FOCAL NEUROLOGICAL DEFICITS (Seizures/Hemiparesis/Aphasia)Rarely patient may have Confusion, Dementia, Lethargy or Coma
2. IgG Ab to Toxoplasma – This should be done for all HIV patients at the time of initial workup.
3. Brain Biopsy – only confirmatory test - patients with failed 2-4 weeks of antitoxoplasma
therapy
INVESTIGATIONS1. CT / MRI – ‘Multiple lesions in Multiple Locations’ Ring Encancing Lesions – inflammation and central
necrosis
D/D of Ring Enhancing Lesions
de
TREATMENTSulfadiazine + Pyrimethamine
(05 to 1.5g P/O q 6th hrly) (200mg loading dose Day 1) ( 75mg P/O OD maintainence)
With Folinic Acid (10mg/day)
Long term Suppressive therapy – Sulfadiazine + Pyrimethamine (2g/day) (25mg/day)
May need to continue maintainence therapy life long in some Or until CD4+T cell count > 200cells/micr.l
Prophylaxis – HIV ,CD4+Tcell count <100c/mi.l, IgG toxoplasma +vePrimary Prevention – HIV , but seronegative for toxoplasma
PROGRESSIVE MULTIFOCAL LEUCOENCEPHALOPATHY It is a late manifestation, seen in 4% of patients with AIDSPATHOGENESISCaused by the JC virus, DNA containing HPV. Only known complication
Approx 90% of general adult population is already exposed to this virus in early childhood, and contains antibodies against it.
Lesions – small foci of demyelination in subortical white matter, which coalesce. Areas – Occipital and parietal lobes, cerebellum, brainstem and rarely Spinal Cord.
CLINICAL FEATURES Protracted course Multifocal Neurological deficits -
With or without mental status changes
SeizuresVisual Field defectsAphasiaAtaxia, and occ. Sensory deficits
INVESTIGATIONS1. CT / MRI – Multiple nonenhancing white matter lesions,
may coalesce, predilection for occipital and parietal.
MRI – decreased signal intensity on T1 - Hyperintensity on T2
2. CSF – non specific changes - CSF PCR for JC virus DNA (sensitivity 76%, specificity 100%)
3. Brain Biopsy – if clinical diagnosis likely, but no viral DNA detected on CSF
Bizarre giant astrocytes with pleomorphic hyperchromic nuclei Altered oligodendrocytes with enlarged nuclei Cells with viral inclusions and myelin loss
FLAIR Images Showing Progression of Progressive Multifocal Leukoencephalopathy
a) Multifocal, high-signal-intensity lesions (arrow) in the right hemisphere of a patient The CSF was positive for JC virus. b) Contrast enhancement is not evident (arrow). c ) 6 weeks later, progression of the white matter lesions (arrow) shows involvement of the uncinate fibers. d )Patchy enhancement with gadolinium (arrow) is noted (predominantly in the right hemisphere
T2 flair MRI brain shows White matter hyperintensity of subcortical U fibers, splenium of corpus callosum in posterior cerebral hemisphereNo contrast enhancementNo mass effectCommon sites: temporal and occipital white matter, Subinsular region, corpus callosum and subcortical U fibers
TREATMENT No specific therapy available for PMLE Improved survival has been seen with HAART
HIV with PMLE
without HAART with HAART
Mean Survival- 3 – 6 months around 2.5 years (>7years*) Patients on HAART may show paradoxical worsening due to IRIS
Only 50% of patients on HAART show any neurological improvement
Other therapies tried – Cytosine, acyclovir, Vidrabine, IFN alphaAll these therapies have shown generally unsatisfactory results
PRIMARY CNS LYMPHOMA Complicate the course of AIDS in upto 5% of patients.PATHOGENESISPCNSL of B cell origin are considered oppurtunistic neoplasms.CLINICAL FEATURESSimilar to Toxoplasmosis – fever, headache , FNDs PCNSL TOXOPLASMA Tempo of evolution slower presents as acute/subacute several days to few weeks Fever usually absent may or maynot be present No response to antitox therapy Show clinical and
neuroimaging imrovement in response to Antitox therapy
INVESTIGATIONS1. MRI > CT – one or more deep lesions
- location – deep, adjacent to lateral ventricle - White matter rather than gray matter
- subependymal extension - predilection for Posterior fossa - Mass effect may be present, surrounding edema rare2. CSF – unhelpful - Monoclonal B lymphocytes by flowcytometry - CSF – EBV virus DNA amplification3. BRAIN BIOPSY – definitve diagnosis
- After a failed therapeutic trial for Toxoplasmosis
4. SPECT SCAN – may be useful.
Corroborative evidence on PCNSL
A-B. 24 year-old man with AIDS Show a solitary large ring-enhancing lesion with mild mass effect and moderate vasogenic edema. The hypointensity of the lesion on T2WI is characteristic of lymphoma. Note that the mass effect and edema is less than expected given the size of the lesion, as is typical for primary brain lymphoma while much more edema and mass effect vs. lesion size is expected in toxoplasmosis.
C-D. 30 year-old man with AIDSshow left temporal lobe vasogenic edema, related to a temporal lobe mass lesion (not shown). There are also bilateral lesions in the caudate nuclei on T2WI (D)(red), with periventricular and ependymal extension of enhancement on the right (C).(green) The ependymal spread is
characteristic of PCNSL
A)POST CONTRAST T1WI B) FLAIR T2WI
C) POSTCONTRAST T1WI D) T2WI
TREATMENT HAART – vigorous attempts to suppress HIV replication are
recommended in all patients with PCNSL
Mass effect – High dose corticosteroid therapy
Radiotherapy – Palliative whole brain radiotherapy
Chemotherapy – Its use remains controversial, trial stages.
VACUOLAR MYELOPATHY VM is the most common cause of spinal cord dysfunction in
untreated patients with AIDS. It is apparent in 25% to 55% of AIDS autopsy series It frequently coexists with HIV Encephalopathy and Distal Sensory
polyneuropathyCLINICAL FEATURES Subacute onset – over weeks or months Gait disturbances, imbalance Ataxia Spasticicity Sphincter dysfunction Examination –Spastic parapareis, Hyperreflexia, Babinski +ve, Loss
of proprioception and vibration sense . No sensory level. Arms are typically spared
VACUOLAR MYELOPATHY VITAMIN B12- sacd
S. Vitamin B12 levels are Normal Decreased
Usually associated with Distal Sensory neuropathy
Not seen
Vacoular changes in myelin sheaths Decreased methylation of histidine and phasphatidylcholine prod.
HIV infected patients may also present with Vitamin B 12 deficiency.
INVESTIGATION nonspecific , to exclude other etiologies
1. MRI SPINE – Cord swelling wtith intramedullary enhancement - T2 signal changes2. CSF – testing for Viral DNA – CMV, VZV, HSV, HTLV 1 & 2
TREATMENT HAART – Viral control can result in improved neurological
function is not well documented in VM. Assistance – Personal
Care of neurogenic bladder, bladder infection Prevention of skin breakdown
Management of limb spasticity, etc.
Sagittal T2-weighted images of the cervical spine- increased signal on T2 extending from C2 though approximately C5.
The axial T2 image- Abnormal signal to be symmetric within the posterior columns of the cord.
C2
C5
Iintramedullary signal enhancement
HIV associated NEUROPATHY Peripheral neuropathies complicate all stages of HIV. Symptomatic neuropathy is seen in 10-15% of patients but
pathological changes of peripheral nerve involvement - almost all AIDS patients
HIV ass. NEUROPATHY
Distal Sensory PN AIDP and CIDP CMV assoc. POLYRADICULOPATHY
NRTI assoc. TOXIC NEUROPATHY
DISTAL SENSORY POLYNEUROPATHYCLINICAL FEATURES Painful burning sensation, with numbness in both feet.Hands spared Depressed or absent ankle jerks, mild pain, temp., vibratory sense loss in
the feet. Symmetrical involvement is a characteristic clinica feature and hands are
usually spared. INVESTIGATIONS – typical clinical features are diagnostic
TREATMENT Reduce exposure to NEUROTOXINS – Ethanol, NRTIs, INH,
Metronidazole, Dapsone, Vincristine Screen for Vitamin B 12 Deficiency, Diabetes Mellitus HAART Pain control – TCAs – Nortiptyline > Amitriptyline - Anticonvulsants – Gabapentin
Help relieve neuropathic pain
Thank you
References1. Neurology in Clinical Practice – 3rd edition(Bradley, Daroff, Fenchal)2. Adams and Victor’s Principles of Neurology- 9th
edition3. Harrison’s principles of Internal Medicine – 17th
edition4. Textbook of neurology- Dounghey5. NACO guidelines for management of AIDS- 20106.WHO guidelines for HIV/AIDS7. World Wide Web